Dupuytren's Practice Blog

 I saw a new blog post by Dr Shaffer posted recently and it is worth considering reading it. The content relates to when is it too early to get RT for Dupuytren's? Now while I know from experience and Dr Shaffers comments the case for Ledderhose is slightly different, however it is good to be knowledgeable that it is not always the right time to have Radiotherapy. 

The Dupuytren's Practice Blog Post

I won't go into the post in detail because that is what the link is for. I have also seen some YouTube videos by Geesis care that I plan on reviewing. There is also a paper on low dose radiation therapy for benign conditions. 

I originally only scanned the article but noticed TGF mentioned which I had covered previously in a post on the pathways linked to the development of Dupuytren's. Be interesting to see whether the proposed mechanism of action of RT / pathways impacted is the reverse of the expected for the cause of Dupuytren's. 

Calorie Restriction to help Dupuytren's and Ledderhose?

A literature review to analyse the link between calorie restriction and pathways associated with Dupuytren's disease

Over recent weeks I have heard several patients talking about calorie restriction and how eating a low calorie diet really seems to help with the pain that they were experiencing with Dupuytren's and Ledderhose and that when they stopped the diet it seemed to get worse. 

The IGF-2 link:

There is some logic behind this, after all I have already discussed how these conditions can be linked to IGF2 and IGF1 is linked to calorie restriction. However further research did not seem to come up with any evidence to suggest a good link between IGF1 and collagen. The only way I could see that the IGF2 information could help is as follows: 

• I know that IGFBP6 binds to both IGF1 and IGF2, albeit more strongly to IGF2, and that calorie restriction causes a decrease in IGF1.

• So of you have less IGF1 then the IGFBP6 is more likely to bind to IGF2, assuming that the concentrations are at a level where the increased availability of IGFBP2 still results in an increased binding affinity for IGF2. 

• So if low IGF1 causes an increase in IGFBP6 binding to IGF2 and therefore decrease the downstream effects of IGF2 one of which is collagen production you may see a difference http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684083/figure/F3/

I think that the above is a little bit of a stretch but you never know. That was all I could find using IGF1 and collagen.

Figure 1: Overview of the impact of TGF-B1 on Collagen production and how calorie restriction impacting IGF-1 levels may result in a lowering of Collagen production.

Calorie Restriction and Collagen:

So instead of that I took a different approach and decided to look for a straight linked between calorie restriction and collagen. Here I managed to find a link, in that the following paper states that calorie restriction results in a decrease in collagen production, perhaps this would also hold true a) in humans b) under conditions where Dupuytren's is present. (Ref 1). I did not have full access to the paper so could not really see what they had done but it also states that this decreased collagen production also has a negative impact on would healing which of course relies, to some extent, on the same pathways as Dupuytren's. This may be a good thing for Dupuytren's or Ledderhose patients.  

The MMPs: 

Another key set of proteins in the extracellular matrix (ECM) is the MMP protein. These are involved in breaking things down and it has been shown that knock-down (removal in cells) of  MMP2 (Ref 2) inhibited cell mediated contraction. Interestingly there have been studies in rats that have shown that a calorierestricted diet results in a decrease in MMP2, so you could argue that a calorie restriction diet will lower MMP2 and that a lowered MMP2 will aid Dupuytren's and or Ledderhose. Furthermore they showed that it appears that calorie restriction also lowers the TGFB1 pathway which I discuss in the IGF2 link at the top. 

Figure 2: The role of MMP2 in Dupuytren's and the potential impact of calorie restriction on Dupuytren's and Collagen production. 

Collagen, the extra-cellular matrix and calorie restriction:

My final search I just thought I would have a look for ECM itself and calorie restriction and see what I could find and I found a couple of very interesting papers which I believe are both free to download. 

The first paper (Reference 4) is looking at the impact of calorie restriction in tumours. Interestingly they found that there was a decrease, as expected in IGF-1 which I have discussed above but they also observed that in calorie restricted mice there was a decrease in MMP2, which as discussed above is linked to the development of Dupuytren's. There was also a decrease in the levels of TGFB-1 which again I have also discussed above. 

Another protein that they mentioned that took my interested was collagen 4. Although Collagen 3 is the main component of the Dupuytren's lumps it is interesting that there are downstream effects on the levels of a collagen type. The second paper I am not going to go into as it basically has similar but less information as in the above paper though it does have a good picture on page 6 (Reference 5). 

The other side of the argument: 

You cannot construct a complete article without looking at both sides of the story. My research into this side was not as extensive because it is hard to find information disproving something that it just an idea but did bring up some interesting points.

The following paper (Ref 6) shows that despite the information I have seen above that TGF-B2 (yes 2 not 1, still looking into this but from what I have seen so far 1 and 2 act through the same pathways) does not affect the collagen levels in Dupuytren's cultures. In fact I am not sure what else to say on this side, if anyone has any information they would like to add then let me know.

Conclusions: 

Would having a calorie restricted diet hurt someone? It might but at the same time you can come off of it and may not have lost anything but you may have gained the used of your foot or stopped your hand from progressing. There is no information out there that says that it will work like that, in fact there is no direct evidence at all linking calorie restriction and Dupuytren's (for or against). The above data is a collection of the information that I could find that linked calorie restriction to pathways that have been linked to Dupuytren's. A lot of this data suggests that there could be some impact but there was nothing there that made me think that it definitely will work. 

As a non-medical professional I cannot endorse having a low calorie diet in general or a as a treatment for these conditions, although the information above suggests that it may have some impact. Note that many of the above studies were in cells or cancer and not in humans and none were related directly to Dupuytren's or related conditions. You should always consult a doctor before starting a very low calorie diet. If a doctor was interested in using this then I would be happy to work with them to look into this.

If any patients have experience of this and would like to share their story it would be great to add the information to the blog.

Other areas of interest: 

There is another signalling pathway called the Wnt signalling pathway. I know from back in my degree that this is using is development and it is still active in adults. I mention this pathway because it has been shown that a high number of Dupuytren's patients have SNPs (differences to everyone else) in genes that are associated with that patients (Ref 7). Although this is as far as the evidence go the Wnt signalling pathway has been linked to diabetes, cell growth and certainly warrants more investigation. 

Reference 1:

Reiser K1, McGee C, Rucker R, McDonald R - 

Access 29-09-2014

J Gerontol A Biol Sci Med Sci. 1995 Jan;50A(1):B40-7.Effects of aging and caloric restriction on extracellular matrix biosynthesis in a model of injury repair in rats.

http://www.ncbi.nlm.nih.gov/pubmed/7814778

Reference 2: 

Biochim Biophys Acta. 2012 Jun;1822(6):897-905. doi: 10.1016/j.bbadis.2012.02.001. Epub 2012 Feb 9. MMP-14 and MMP-2 are key metalloproteases in Dupuytren's disease fibroblast-mediated contraction.

Wilkinson JM1, Davidson RK, Swingler TE, Jones ER, Corps AN, Johnston P, Riley GP, Chojnowski AJ, Clark IM.

http://www.ncbi.nlm.nih.gov/pubmed/22342364

Reference 3: 

Calorie Restriction Reduces MMP-2 Activity and Retards Age-associated Aortic Restructuring in Rats , Mingyi Wang et al

http://circ.ahajournals.org/cgi/content/meeting_abstract/114/18_MeetingAbstracts/II_335-b

Reference 4:

Caloric restriction reduces growth of mammary tumors and metastases - Mariana S. De Lorenzo et al

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165123/

Reference 5: 

Molecular Mechanisms of Calorie Restriction’s Protection against Age-related Sclerosis, Elena Chiarpotto et al - http://onlinelibrary.wiley.com/doi/10.1080/15216540601106365/pdf

Reference 6: 

Enhanced Dupuytren's disease fibroblast populated collagen lattice contraction is independent of endogenous active TGF-β₂ Raymond Tse¹⁴, Jeffrey Howard¹²⁴, Yan Wu¹⁴ and Bing Siang Gan^1234*

http://www.biomedcentral.com/1471-2474/5/41

Reference 7: 

Wnt Signaling and Dupuytren's Disease, Guido H. Dolmans,  et al

http://www.nejm.org/doi/full/10.1056/NEJMoa1101029

Is Dupuytren's in your DNA?

As many of you will know I am in a science based job and I did my undergraduate degree in Molecular Genetics. Today I want to cover whether there is a genetic element to Ledderhose and Dupuytren's. As always the information available on Ledderhose is not there and so I am looking at Dupuytren's as if this is a predisposition at the genetic level then it seems likely that this is the same for both.


I felt that a good place to start here is the book - Dupuytren's Disease and Related Hyperproliferative disorders where: 


Chapter 11 - The Genetic Basis of Dupuytren's: An introduction: 

First of all they start by saying that virtually all diseases are a combination of Hereditary and environmental factors and from this I am concluding that this is why it is capable of skipping generations or like in my Ledderhose popping up from nowhere.

The familial incidence of this disease does vary and in Scotland, Sweden, Iceland and Norway for example it is high and several papers have put it as high as 44% and 74% (Skoog 1948 and Gudmundsson et al 2000) They also look in a variety of ways at 1000 patients in a study themselves where they observe that 40% of these have a family history of the disease although I cannot see any note of how recent this family history needs to be they do note that in these cases onset seems to be earlier and develop quicker. Interestingly, bearing in mind other posts that I have done on susceptibility, they do see 11% of cases with diabetes but there is NO link to alcohol or smoking.

From my point of view it makes some sense that if you have a family history you are more likely to suffer from this earlier. I think this because if you do have a genetic background that means then the balance between hereditary and environment is already heavily shifted towards you getting it so that only a slight environmental factor such as trauma, that in most cases would not result in the development of these diseases does for you because of the increased chance you have.

In their concluding comments of this section they do state that there are on-going studies where many countries are collaborating to try and tease out some of the mutations that might lead to increased odds of Dupuytren's and Ledderhose.

Interestingly research has already been done to look into some of the obvious candidates such as TGF-beta (see my picture at the bottom of this post as to why looking at this makes sense) and actually they have not seen a link between the two. This means that the problem lies elsewhere. In Chapter 12 this is discussed further to show that not only have they look at TGF-Beta but other members of that pathway and again no link is seen. This is somewhat surprising as on the one hand you would think that an increased level of TGF-B would result in an increased likelihood of Dupuytren's but all that the above results mean is that this cannot initiate the disease and but I reckon a higher level of TGF would result at least in faster progression of the disease.

It is obvious that there is some genetic element and that it some cases it plays a huge role, in some cases entire countries seem to be at risk once they have reached 50 and I guess these countries are where this research needs to be continued.

Genetics is not the be all and end all of getting these diseases, I on the one hand have no history of either Ledderhose or Dupuytren's but I have spoken to several people with extensive backgrounds of the disease. Yet in all the people I have spoken to only 1 has had a younger age of onset and they had a clear case of massive trauma to the site shortly beforehand. So although there clearly is an increased risk of getting a bent finger or a lump in your foot if you Mum and Dad did, if they didn't it doesn't mean you're safe.